There are gaps in understanding of the influences of stressors during puberty on the later development of psychiatric disorders in adulthood. It has recently been discovered that particular stressors during the pubertal period in female mice result in an enduring alteration in behavioral response to ovarian hormones, including behaviors related to depression and anxiety. Because of the importance of this developmental stage in adult behaviors related to mental health that are regulated by the ovarian hormones, the acute physiological effects of particular pubertal stressors that do or do not influence behavioral response to ovarian hormones in adulthood will be tested. The long-term goal of this project is to discover the mechanisms by which particular stressors during a narrow, pubertal period alter adult, behavioral responses to ovarian hormones using animal models. The central hypothesis is that particular stressors during a well-defined, pubertal period induce acute, physiological changes that then result in an alteration in behavioral responses to ovarian hormones, including the response to estradiol on depression- and anxiety-like behaviors. The rationale for this prediction is that particular pubertal stressors during a narrowly defined period dramatically alter the effects of ovarian hormones on a variety of behaviors, and there must be differences in the acute physiological responses of the animals to these stressors at these times. We have observed elimination of, or alteration in, behavioral responses to estradiol in female mice exposed to particular stressors during puberty. This is consistent with work by others that the pubertal period is a critical time in the development of adult behavioral response to ovarian hormones, but the finding that a transient stressor at this time can have permanent effects on behavioral response to ovarian hormones is novel. In the specific aim, hypotheses concerning the cellular processes that are responsible for the alteration in hormonal response in adulthood will be tested. Specifically the relationship of immune challenge-induced sickness behavior, thermoregulatory responses, and changes in plasma and brain cytokines to the altered behavioral response to ovarian hormones will be assessed. These experiments will lead to direct tests of the mechanisms responsible for the altered behavioral response to ovarian hormones that endures into adulthood. This research will advance the field of Behavioral Neuroendocrinology by identifying influences during the pubertal period on adult behavioral response to ovarian hormones and the mechanisms of these influences. The research is innovative, because it investigates the causes of enduring influences of stressors during a well-defined, pubertal stage of development on behavioral response specifically to ovarian hormones. This work is significant, because it will serve as a model for studies of other mental health-related endpoints that are influenced by estradiol, including addiction and other personality and psychiatric disorders. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to mental health, because particular stressors during the pubertal/adolescent period decrease response to ovarian hormones on mental health-related behaviors in adulthood. The research is relevant to the mission of NIMH, because it will provide understanding of the mechanisms by which some pubertal stressors influence adult behavioral response to ovarian hormones.